Biomedical Engineering Reference
In-Depth Information
is less well understood. As with BMPs, multiple
forms of the FGFs are expressed in the peri-
chondrium. FGFR
dogs, a single dose of bFGF injected into the
fracture sites resulted in increased callus area
and BMC and signifi cant recovery in strength
by week
is expressed in prehyper-
trophic and hypertrophic zones and FGFR
1
by
proliferating chondrocytes. More recently, the
actions of FGF signaling have been shown to
depend on the stage of chondrocyte differentia-
tion and the nature of the individual ligands.
Thus, specifi c receptors are expressed and
interact with specifi c ligands in chondrocytes
only at specifi c stages of differentiation. Studies
of limb cell cultures have indicated that FGF
signaling interacts with both the Ihh/PTHrP
and the BMP signaling systems in a complex
network. FGF signaling seems to accelerate
both the onset and the pace of hypertrophic
differentiation, in actions that are antagonistic
to those of BMPs, and to regulate chondrocyte
Ihh expression and hypertrophic differentia-
tion. BMP, on the other hand, seems to rescue
the remaining proliferating and hypertrophic
chondrocytes in achondroplastic mice. This
has led to the conclusion that the interaction of
BMP and FGF in the growth cartilage regulates
the rate of chondrocyte differentiation and
proliferation [
3
. Thus, FGF has therapeutic poten-
tial to enhance bone healing after surgery or
injury.
16
2.2.5.2 Wnts (Wingless)
Wnts are
-kDa cysteine-rich, secreted
glycoproteins that are closely associated with
both the cell surface and the ECM [
39
- to
46
].
Wnts are considered one of the major morpho-
genetic gene families responsible for appropri-
ate embryonic development [
161
,
214
]. Genetic
studies fi rst performed in
Drosophila
have
defi ned the function of this gene family. In
Dro-
sophila
, the wingless gene is required for
normal patterning in the adult and larval body
segments [
146
]. The lack of this wingless
gene results in the deletion of the posterior
region of each body segment [
13
,
14
,
162
]. Ectopic
gene expression in
Xenopus
and gene knockout
models in mice have since led to further under-
standing of the crucial role that Wnts play in
organ development, segmentation, CNS pat-
terning, cell fate and growth, limb develop-
ment, and organization of asymmetric cell
divisions [
14
,
162
].
The intracellular effects of FGFs are medi-
ated by two signaling pathways: the mitogen-
activated protein kinase/ERK kinase
148
)
pathway and the Janus kinase-signal trans-
ducer and activator of transcription (JAK-
STAT) pathway [
1
(MEK
1
11
,
45
,
168
,
216
]. To date, approxi-
mately
Wnt genes have been identifi ed in
species ranging from
Caenorhabditis elegans
to
humans [
100
]. The JAK-STAT
signaling pathway mediates the ability of FGF
signaling to inhibit chondrocyte proliferation
and enhances hypertrophic chondrocyte apop-
tosis, whereas the MEK
152
,
165
,
182
].
Once the Wnt proteins are secreted, they
bind to two families of cell-surface receptors,
the Frizzled (Fzd) receptors and the low-density
lipoprotein (LDL) receptor-related proteins
(LRPs). The Fzd receptor generally consists of
an extracellular cysteine-rich domain (CRD)
that binds the specifi c Wnt protein. This recep-
tor also consists of a seven membrane spanning
domain on the cytoplasmic tail towards the
carboxy-terminus of the protein. In contrast,
the LRP-
216
pathway mediates FGF
inhibition of hypertrophic differentiation.
A number of studies have examined whether
FGF has utility in promoting bone formation.
Systemic low doses of basic FGF (FGF-
1
) stim-
ulate endosteal and endochondral bone forma-
tion, but depress periosteal bone formation in
growing rats [
2
145
,
156
]. Local administration
receptors have a single trans-
membrane domain [
5
and -
6
of acidic FGF (FGF-
) increases new bone for-
mation and bone density, whereas systemic
FGF-
1
]. A variety of secreted
proteins, such as Frizzled-related proteins
(sFRPs), Wnt inhibitory factor
200
appears to restore bone microarchitec-
ture and prevent bone loss associated with
estrogen withdrawal [
1
), and
Cereberus, have been shown to be moderators
of extracellular Wnt signaling. The Dickkopf
(DKK) protein also exerts regulatory action by
directly binding to the LRPs, thereby blocking
signal transduction [
1
(WIF
1
50
]. Both FGF-
1
and
FGF-
appear immediately at injury sites after
fracture. FGF-
2
was shown to improve bone
healing in a study that induced a large seg-
mental defect and in another with a metaphy-
seal fracture. In a
2
].
When the ligand becomes bound to the Fzd
receptor, three signaling pathways are acti-
11
32
-week study of beagle
